OBJECTIVE: Compliance plays a major role in chronic conditions to help achieve a full course of therapy. All chronic diseases have adherence to prescribed drug therapy as obstacles to treatment. Potential consequences of non-adherence include relapse, treatment resistance, suicide, impairment of functioning (work, interpersonal) and worsening of comorbid illnesses. All of these potential consequences can have a significant economic burden on the society. So we intended to evaluate the clinical efficacy of fluoxetine 180 mg (2 x 90 mg tablets) once a week in ambulatory patients stabilized on Fluoxetine 40 mg daily. METHOD: Thirty patients stabilized on fluoxetine 40 mg daily were evaluated in a mirror image design. They were switched to fluoxetine 180 mg (2x 90 mg tablets) once a week. Steady state serum drug concentration and Clinical Global Impression-Severity (CGI-S), medication compliance and patient attitude survey were obtained before and after the switch. RESULTS: Mean age of the patients was 41.7 + 11.7 years, with 8 males and all of them met DSM IV criteria for major depression. Mean duration of depression was 8 +3 years. Fluoxetine/Norfluoxetine serum concentrations were 261 + 185 and 295 + 206 ng /ml (P=.21.). CGI-S was 2.5 + 0.7 and 2.6 + 0.7 before and after the switch. Compliance before the switch was 73.6 % before and 91% after the switch. This difference was statistically significant at p<0.0001 (t=-7.8651, df=29). 41% of the patients strongly agreed that weekly dosing regimen was preferred over daily regimen. CONCLUSION: Our evaluation indicates that once a week dosing is as equally clinically efficacious as a daily dose in the management of major depression in our population of ambulatory patients. Significant improvement in compliance can only have a positive impact on the health outcome and costs.